Low resolution, YAC-based maps of portions of the human genome, including several complete human chromosomes, have been developed over the past several years. However, the techniques for the creation of detailed, high resolution maps showing the locations of important sequence structures and the locations, orientation and transcription frame of genes, have not yet been developed. This application proposes a limited feasibility study to test the concept of developing high resolution, DNA sequence-based maps of human chromosomes based upon a novel strategy called GSS (Genome Sequence Sample) mapping. This strategy depends upon the identification of cosmid clones from chromosome-specific libraries by hybridization with YAC clones from a minimum tiling path chromosome map, the development of high depth cosmid contigs by individual clone fingerprinting, and the direct end-sequencing of cosmid clones to generate a set of ordered sequence fragments. This high resolution map will allow the identification of gene sequences and sequence motifs by computer-based search algorithms, the preparation of essentially continuous STS markers for any region of the genome, and provide template material for the eventual complete DNA sequencing of human chromosomes. The initial focus of this project will be the development of a high resolution map of human chromosome 11 but will include other regions of the genome of biological interest as time permits. This project will also develop high throughput, balanced automation systems for the megabase DNA sequencing and for high resolution physical mapping.